In vivo characterization of connective tissue remodeling using infrared photoacoustic spectra

Abstract

Premature cervical remodeling is a critical precursor of spontaneous preterm birth, and the remodeling process is characterized by an increase in tissue hydration. Nevertheless, current clinical measurements of cervical remodeling are subjective and detect only late events, such as cervical effacement and dilation. Here, we present a photoacoustic endoscope that can quantify tissue hydration by measuring near-infrared cervical spectra. We quantify the water contents of tissue-mimicking hydrogel phantoms as an analog of cervical connective tissue. Applying this method to pregnant women in vivo, we observed an increase in the water content of the cervix throughout pregnancy. The application of this technique in maternal healthcare may advance our understanding of cervical remodeling and provide a sensitive method for predicting preterm birth.

Keywords: cervical examination; photoacoustic endoscopy; spectroscopy; tissue hydration.

Fig. 1

PANIR system. (a) Setup of the PANIR system. BB, beam block; CS, control system; DM, dichroic mirror; FC, fiber coupler; LF, longpass filter; Nd:YAG, Nd:YAG laser with a frequency tripling module; OPO, optical parametric oscillator; SM, stepper motor. (b) Photograph of a PANIR probe. (c) Schematic of the components in the probe. BC, beam combiner; MMF, multimode fiber; PD, calibrated photodiode; UT, ultrasonic transducer.

Fig. 2

PANIR spectra quantify the hydration of hydrogel. (a) PANIR spectra measured from hydrogel phantoms made of water and gelatin with different fractions. (b) and (c) Water contents measured at (b) 1460 nm and (c) 1940 nm versus the preset values.

Fig. 3

Effects of scattering simulated by the Monte Carlo method. (a) Effect of scattering on the spectrum. We measured the PANIR spectrum of distilled water (blue) and calculated its spectrum distorted by scattering (red), comparable with the degree found in human skin. (b) Effect of scattering on the distributions of fluence in a medium. The absorption at 1460 nm is so strong that the scattering leads to only a small perturbation of the distribution of fluence. S1180, simulated at 1180 nm in the scattering medium; S1460, simulated at 1460 nm in the scattering medium; T1180, simulated at 1180 nm in the transparent medium; T1460, simulated at 1460 nm in the transparent medium. For illustrative purposes, T1460 and S1460 are divided by a factor of two. (c) Quantified water contents for the human tissue and the hydrogel phantoms. The transparent model underestimates the water content of the scattering medium by $\sim 1\%$. The red error bar and the black error bar, respectively, show the standard deviations contributed by the cross-sectional change of scattering among the tissue samples ($n=16$) and by the heterogeneity of the hydrogel phantoms ($n=10$). SP, scattering phantom; TCS, tissue corrected for scattering; TP, transparent phantom; TUCS, tissue uncorrected for scattering. ***, $P<0.001$. NS, nonsignificant.

Fig. 4

PANIR spectra quantify cervical remodeling. (a) PANIR spectra measured from the cervix of a pregnant woman at five gestational time points. (b) Longitudinal changes of water contents in the cervices of pregnant women ($n=205$), shown as gray lines. The red solid line indicates the fit at the unit level of the generalized linear model to the measured data. The black dashed line represents the level of intercept.